Werner schulemann



Patented Feb, 18, 1930 "UNI E STATES- PATENT OFFICE WERNER SCHULEMANN, OF VOHWINKEL-HAMMERSTEIN, AND FRlITZ SCH6NH6FER AND AUGUST WINGLER, F ELBERFELD, GERMANY, ASSIGNORS TO WINTHROP CHEMICAL COMPANY, INC., OF YORK, N- Y.

- manureo'ronn on unwrrmnneonurrcnn Pnonucrs no Drawing. Application filed August 2 4, rea iyserin in. 52,230, and in Germany September. 11., 1924.

The present invention relates to pounds of the general formula:

line nucleus may be further substituted, and v to a process of preparing the same.

We havefoundthat these compounds are exceedingly valuable .and effective new reme dies for use in therapy. Q The manufacture of our .new compounds can be effected in several ways. For instance, a compound ofthegeneral formula:

wherein represents hydrogen, an alkyl group, or an amino-alkyl grou and wherein the quinoline nucleus may be urther substituted may .be caused to be actedupon by a compound of the general formula 3 wherein represents halogen, R -analliylene residue in which the hydrogen atoms may be substituted a monovalent substituent such as'the hydroXyl ,group and R and;B, repr' esent hydrogen, an alkyl grouper: an amino-v alkylrgroup' and wherein the quinoline-nucleus may be substituted or not. 1

- Instead of thelast mentioned compound one may use a salt of this compound with com-f a compound of the general 'formula:

, amino-derivatives.

ferent steps, for example by first acting on wherein. X represents hydrogen, an alkyl group, or an; amino-alkyl grou and wherein the quinoline nucleus may be urther substituted, with'ethylene oziide or a halogenated alcohol and converting the hydroxy-alkylamino. compounds, thus obtained, into the corresponding amino-alkyl-amino compounds in'tli'e customary manner. It will be understood that yet another method of executionof the present inventior'rconsists in the conversion'of intermediate products suitable for the manufacture of the above mentioned aminoderivatives of the quinoline series, their derivatives, substitution products and equivalents into more strongly basic aminoderiva'tives thereof according to any of the methods outlined above, or according to. any other customary method, subsequently transforming the intermediate compounds thus obtained intojthe said more strongly basic Both primary and secondary amino-derivatives of the quinoline series, their derivatives, substitution products and'equivalents can be converted into said more strongly basic amino-derivatives. Moreover, it' is also possible to use amines which contain not only'one but several amino cups and likewise the side-chain" carry- H mg the aliphatic nitrogen, whether occurring only once or several times, may be either straight or branched and thealiphatic nitrogen atom may happen to be in the B or y position or even further" removed from the aminogroupsq I I I Emampl e 1 Diethylaminoethyl-S-aminoquinoline an inorganic acid or a substitution product I thereof, such as the bromo-ethyl-phthalimide compound. In the last case the phthalic acid is to be split off subsequently.

The manufacture can be carried out in dit (CzH5)1NGHz-CHr-NH 14.4 parts by Weight of ortho-aminoquin oline are heated on an oil-bath at 120-140 I v for 24 hours with 17.2 parts by weight of the hydrochloride of diethyl-aminoethyl ch1oride. The melt is boiled out with 200 parts of water and filtered. The filtrate" is cooled and salted outwith potassium carbonate, the resinous mass which is thus precipitated being extracted with ether. The ether solution is thereupon washed several times with water, then dried and the ether distilled ofil The contents of the vessel are steam distilled until all traces ofo-amino-quinoline are eliminated. Thereupon theresidue is again extracted with ether and after distil- "5 worked up;

7 \It is aviscous oil, boiling at 175-183 C.

. The preparation of chloride.

ling off the ether the remaining oil is fractionated and redistilled, boiling at 180-182. C. under 4-5 mm. pressure. The resulting com ound is a light oil which dissolves in'dllute hydrochloric acid very readily.

Example '2 5 14.4 parts by weight of o-aminoquinoline and 15.05 parts by weight of the hydrochloride of a-dimethylamino-fi2-methyl- -chlorbutane are caused to react as in the above example and the. resulting product is similarly under 2-8 mm. pressure.

j Ewample 3 The compound of the formula is prepared by causing 6-m'ethoxy-8-aminoquinoline to react with a-diethvlamino-B-chloropentane.

the latter chloroalkylamine is efl'ected by the decomposition of diethylamino-ethyl chloride with the sodium compound of aceto-acetic ester,'with the subsequent splitting up of diethylaminoethylacetoacetic ester into a-diethylamino-8-pentanone, which after reduction of the keto group hydroxy- -chloropropane the alcohol is then distilled ofi and the residual ester worked up in the customary manner. The ester is dried over anhydrous sodium sulfate after which it distils as a colorless liquid, retaining a slightly basic odor and boiling at 115120 C. under a pressure of 5 mm. For the production of the corresponding ketone referred to above, the ester is heated'on the waterbath with ten times its weight of 10 per cent sulfuric acid, until the evolution of carbon dioxide is complete. The aminoketone is isolated from the sulfuric acid solution by rendering the same alkaline with potassium carbonate, distilling with steam and salting out the aqueous distillate with potassium carbonate. The aminoketone is dried over potassium carbonate and distilled giving a colorless liquid boiling at 83-85 C. under 15 mm. pressure. Reduction with sodium amalgam at ordinary temperature in acetic acid solution furnished the amino-alcohol, a liquid of boiling point 97 C. under 15mm ressure and this is converted into a-diet ylamino-S-ehloropentane by heating for 6-8 hours with an excess of thioxyl chloride in benzene solution. The product is isolated from the benzene solue tion by shaking with water and salting out the a ueous solution with potassium carbon ate w ile cooling the whole with ice. It is easily transformed, especially on warming,

into a solid quaternary compound and is converted into the hydrochloride with dry hydrochloric acid gas in ether or benzene solution, without the necessity of effecting distillation. The crude hydrochloride melts at 93 C. For the reaction with 6-methoxy-8- aminoquinoline, 174 parts by weight of the latter are melted with 217 parts by weight of the above hydrochloride and heating is con- 1 tinued at 120130- C. for some 8 hours with continuous stirring. The reaction product is dissolved in water and worked up as described in Example 1. The quinoline compound thus obtainedis a viscous yellow oil which boils. under 2 mm. pressure at 189190 C. p I

Ewample 4 For the manufacture of a-diethylamino-fl- 92.5 parts by weight of epichlorhydrin in four times the amount of water are vigorously stirred with a neutral aqueous solution of 109.5 parts by weight of diethylamine hydrochloride at ordinary temperature until all the epichlorhydrine has been taken up by the solution. The solution is thereuponrendered alkaline at 05 C. with the equivalent amount of potassium carbonate and stirring is maintained for a further 12 hours at the same temperature. The practically completely clear solution is cooled well with ice and salted out with otassium carbonate, the oil which separates eing extracted with ether. After thoroughly drying over anhydrous magnesium sulfate the ether together with any remaining diethylamine is evaporated in vacuo. I

The remaining chloroxyalkylamine, an extremely decomposable liquid, is converted at once into the hydrochloride in ether or benner are treated as described in Example 4.

zene solution. The chloride is not stable in the free state, being transformed almost momentarily especially on warming, into a solid quaternary compound.

For the decomposition with 6-methoxy-8- aminoquinoline, 114 parts by weight of the latter and 202 parts by weight of the crude hydrochloride of a-diethylamino-B-hydr0xy- -chloropropane obtained in the above man- The quinoline compound thus obtained is an orange-yellow viscous oil, boiling at 225- 227 C. at 2 mm. pressure.

Example 5 188 parts by weight of 6-ethoxy-8-aminoquinoline are heated with 149 parts by weight of a-dimethylamino-fi-methyl- -chlorobutane with the addition of a mixture of equivalent amounts of magnesium and barium oxides, to 120130 C. for some 8 hours with constant stirring. The reaction product is taken up in dilute hydrochloric acid and the hydrochloric acid solution is further treated as described in Example 1. The quinoline compound thus obtained is a yellow viscous oil boiling at 204 at 1 mm. pressure.

Ewample 6 r is distilled in vacuo, boiling at 179-180 C.

at mm. pressure. The distillate is a viscous yellow oil, easily soluble in acids.

We claim 1. As new products the compounds of the general formula:

wherein X represents hydrogen, an alkyl group,an amino-alkyl group, or other monovalent substituent; R represents an alkylene residue in which the hydrogen atoms may be substituted by monovalent substituents such as the hydroxyl group; R, and R represent hydrogen, an alkylgroup, or an amino-alkyl group; and wherein the quinoline nucleus may be further substituted. 7 2, As new products the compounds of the general formula:

N R r N Z RQ wherein X represents hydrogen, an alkyl group, an amino-alkyl group,'or other monovalent substituent; R represents an alkylene residue in which the hydrogen atoms may be substituted by .m0nova1entsubstituents such as the hydroxyl group; R and R represent hydrogen, an alkyl group, or an aminoand wherein the quinolinej nualkyl group;

e further substituted.

cleus may 3. As new products thecompoundslofth general .formula 1 Y 1 NJ wherein X represents hydrogen or an alkyl group; R an alkyleneresidue containing at least two but no more-than five carbon-atoms and in which one of the hydrogen atoms may be substituted'by a hydroxyl group; R and R represent hydrogen atomsor methylor ethyl groups; and wherein the quinoline nucleus may be further substituted.-

general formula wherein X represents hydrogen or an alkyl group; R an alkylene residue containing at least two but no more than five carbon atoms and in which one of the hydrogen atoms may be substituted by a hydroxyl group; R and R represent hydrogen atoms or methylor iis 4. As new products the compounds of wherein X represents hydrogen or an alkyl v I group; R anjal'kylene residue containing at, {least two bu'tfn o:morefthanfive"carbon atoins and in which one of the hydrogen atolns may be substituted by a hydroxyl group; R and R represent. hydrogen atoms ormetl'iylorethyl groups; and y represents a hydrogen V wherein X represents hydrogen or an alkyl ethyl groups; and wherein the quinoline nu- I I cleus may be further substituted.

5. As'new products the compounds of the general formulazf atom, an alkoxyor a'hydroxyl group.

general formula group; R an alkylene residue containing at least two but no more than five carbon atoms and in which one of the hydrogen atoms may be substituted b a hydroxyl group; R and R represent hyc rogen atoms or methyl or ethyl groups; and 3 represents amethoxyor ethoxy group. 7 I

7, As a new product the compound of the formula being a viscous yellow iLbOiling under a pressure of 2 at. a temperature of our hands. 1

WERNER SCHULEMANN. FRITZ SOHONHGFER.

I AUGUST WINGLER.

6'. As new'products the compounds of the i i In testiniony whereof we have hereunto set 

